This invention relates to a novel process for the production of alpha-arylpropionic acids. The invention is particularly useful for the production of anti-inflammatory drugs such as 2-(4xe2x80x2-isobutylphenyl)propionic acid, more commonly known as ibuprofen.
Ibuprofen is a well-known non-steroidal anti-inflammatory drug which has been converted from ethical, i.e., prescription, to over-the-counter status. Various processes are known for the production of ibuprofen using 4-isobutylacetophenone as a starting material. Thus, for example, British Patent 971,700 and corresponding U.S. Pat. No. 3,385,886, both assigned to Boots Pure Drug Company, PLC, show the production of phenylalkane derivatives such as ibuprofen in which the first step of the process is the reaction of an alkylbenzene with acetyl chloride in the presence of aluminum chloride to produce an alkylacetophenone which is then subjected to any of various series of subsequent reactions to produce the desired derivative.
Arylpropionic acids have been formed by the carbonylation of the respective arylethyl alcohol. For example, Japanese Kokai Patent No. SHO 55 [1980]-27147, published Feb. 27, 1980 and assigned to Mitsubishi Petrochemical Co., discloses the formation of ibuprofen by reacting 1-(4xe2x80x2-isobutylphenyl)ethanol with carbon monoxide and water in the presence of a hydrogen fluoride catalyst. Japanese Kokai Patent No. SHO 59 [1984]-95238, published Jun. 1, 1984 and assigned to Mitsubishi Petrochemical Co., teaches the formation of alpha-aryl-substituted propionic acids, by reacting an alpha-aryl-substituted ethanol with carbon monoxide and water, alcohol, or phenol, in the presence of a palladium catalyst. An acidic compound such as hydrogen chloride may be added as an auxiliary catalyst and a solvent such as benzene may also be used. The disclosure includes a comparative example in which ibuprofen (not included within the invention) is obtained in very low yield, i.e., 17.1%, when made utilizing the described process. Japanese Kokai Patent No. SHO 59 [1984]-95239, published Jun. 1, 1984 and assigned to Mitsubishi Petrochemical Co., discloses the formation of alpha-(6xe2x80x2-methoxy-2xe2x80x2-naphthyl)propionic acid by reacting alpha-(6xe2x80x2-methoxy-2xe2x80x2-naphthyl)ethanol with carbon monoxide and water in the presence of a palladium catalyst and an acidic compound, e.g., hydrogen chloride. The patent publication also states that if a non-halogen-containing acidic compound is used, it is desirable to add an ionizable metal halide to the reaction.
Japanese Kokai Patent No. SHO 56[1981]-35659, published Sep. 4, 1978 and assigned to Ferrel International Societe Annonim, discloses an anhydrous method of producing a 2-(4xe2x80x2-isobutylphenyl)propionic acid ester by treating 1-(4xe2x80x2-isobutylphenyl)ethanol (IBPE) with carbon monoxide in a solution containing an alkanol and a catalyst such as palladium bis(triphenylphosphine) dichloro complex. The solution may also contain up to 10% of a mineral acid such as hydrogen chloride.
British Patent 1,565,235, assigned to Mitsubishi Petrochemical Co. discloses a process for producing alpha-arylpropionic acids which have an anti-inflammatory, analgesic or antipyretic effect. The process comprises reacting an arylethylene with carbon monoxide under pressure in the presence of a carbonylation catalyst and in the presence of water and/or a lower alcohol to carbonylate the arylethylene into the alpha-arylpropionic acid. The starting materials for the arylethylenes can be prepared such as by the dehydration of arylethyl alcohols or by the dehydrohalogenation of arylethyl halides. The arylethylenes can be purified by means of a single distillation or re-crystallization to obtain the products with a sufficiently high purity to be used as the starting material for the subsequent carbonylation step. An example in the patent describes the dehydrohalogenation of alpha-(4-isobutylphenyl)ethyl chloride to obtain 4-isobutylstyrene and then carbonylating 4-isobutylstyrene in the presence of water, methyl alcohol, hydrogen chloride, and bis(triphenolphosphine)dichloropalladium (II).
In copending, commonly assigned U.S. Ser. No. 158,141, filed Mar. 4, 1988, 2-(4xe2x80x2-isobutylphenyl)propionic acid, i.e., ibuprofen, is prepared by carbonylating 1-(4xe2x80x2-isobutylphenyl)ethanol (IBPE) with carbon monoxide in an acidic aqueous medium at a temperature of at least about 10xc2x0 C. and a carbon monoxide pressure of at least about 500 psig, and in the presence of 1) a catalyst consisting essentially of a palladium compound in which the palladium is complexed with at least one acid stable, monodentate phosphine ligand freely miscible with the organic phase of the reaction medium; 2) dissociated hydrogen ions from an acid which is substantially completely ionizable in a dilute aqueous solution such that the molar ratio of hydrogen ions to IBPE added to the reaction zone is at least about 0.15 and the mole ratio of hydrogen ions to water is at least 0.026; and 3) dissociated halide ions such that the molar ratio of halide ions to IBPE added to the reaction zone is at least about 0.15.
the process is immediately described above for preparing ibuprofen by carbonylating 1-(4xe2x80x2-isobutylphenyl)ethanol is generally a multi-stage process in which the carbonylation reaction to produce ibuprofen is integrated with a method of producing IBPE from isobutylbenzene. Thus, isobutylbenzene is subjected to Friedel-Crafts reaction with an acetylating agent such as acetic acid, acetic anhydride, acetyl fluoride, acetyl chloride, acetyl bromide, methyl acetate in the presence of the Friedel-Crafts catalyst such as hydrogen fluoride to produce 4xe2x80x2-isobutylacetophenone (IBAP) which is subsequently reduced with hydrogen in the presence of a hydrogenation catalyst or with a reducing agent containing available hydrogen, to obtain IBPE.
An alternative process for producing alpha-aryl-propionic acids from the carbonylation of the respective 1-aryl ethyl alcohols is the carbonylation of secondary benzyl halides to the corresponding carboxylic acid. In such a known process, the secondary benzyl halides are carbonylated in the presence of a carbonylation catalyst in a basic medium. For example, in an article xe2x80x9cCobalt-Catalyzed Synthesis of Alpha-Arylpropionic and Diarylacetic Acidsxe2x80x9d, Journal of Organometallic Chemistry 282 (1985) 277-282, there is disclosed the cobalt-catalyzed carbonylation of ArCH(R)X (Rxe2x95x90CH3, C6H5; Xxe2x95x90Cl, Br) in alcoholic solvents under atmospheric pressure of CO. It is stated therein that selective, high yield synthesis of the corresponding acids can be achieved within a very narrow range of experimental conditions. Similarly, U.S. Pat. No. 4,536,595 and related European Patent Applications 76,721 and 76,722 disclose forming alpha-arylpropionic acids such as ibuprofen by carbonylating the respective secondary benzyl halides in the presence of a cobalt hydrocarbonyl catalyst and an anhydrous alcoholic solvent. U.S. Pat. Nos. 4,152,352 and 4,351,952 disclose the formation of arylpyruvic acids by reacting an arylmethyl halide with carbon monoxide in the presence of a cobalt carbonyl catalyst and a base. U.S. Pat. No. 3,974,202 discloses producing an alkyl ester of arylacetic acid by reacting the arylmethyl halide with CO and an alcohol in basic reaction medium in the presence of a cobalt catalyst. U.S. Pat. No. 4,713,484 discloses the formation of carboxylic acid salts by carbonylating an organic halide with an alcohol, CO, and a base in the presence of a palladium catalyst and an excess of tertiary phosphine.
The process for carbonylating the arylalkyl halides to carboxylic acids in base medium has several disadvantages. For one, the carboxylic acid salt of an alkali metal is formed instead of the acid. Consequently, the acid has to be obtained in a separate step by acidification of the salt such as with mineral acids. Additionally, reactions on the arylalkyl halides under carbonylation conditions often result in double carbonylation which leads to the formation of pyruvic acids. Several of the patents mentioned above are directly concerned with the formation of pyruvic acids. Additional disadvantages are that the reactions are not selective over a broad range of reaction conditions and, thus, often a narrow range of conditions must be employed to obtain better yields and selectivity of the desired product.
A process for producing alpha-arylpropionic acids, in particular those of special interest to the pharmaceutical industry as anti-inflammatory, analgesical, antipyrethical agents, etc., and which would be free of the disadvantages of the processes of the prior art such as described above, would inevitably find wide usage. The development of such a process is the primary objective of the present invention.
In accordance with this invention, alpha-arylpropionic acids are prepared by carbonylating the corresponding 1-arylethyl halides in aqueous acidic medium. The invention is useful in the preparation of 2-(4xe2x80x2-isobutylphenyl)propionic acid, i.e., ibuprofen, by carbonylating 1-(4xe2x80x2-isobutylphenyl)ethyl halide with carbon monoxide in an acidic aqueous medium in the presence of a palladium catalyst. Moreover, in the formation of ibuprofen from isobutylbenzene, a two-step process has been developed comprising (1) a haloalkylation reaction in which isobutylbenzene is reacted with a haloalkylating agent such as acetaldehyde with hydrogen chloride to form 1-(4xe2x80x2-isobutylphenyl)ethyl chloride and, (2) a carbonylation in which the 1-(4xe2x80x2-isobutylphenyl)ethyl chloride is carbonylated in aqueous acid medium in the presence of a palladium catalyst to ibuprofen.
In its broadest aspect, the present invention is directed to the production of alpha-arylpropionic acids having the formula: 
wherein AR represents phenyl or a polynuclear aromatic such as naphthalene and which can be substituted with nonreactive groups including alkyl, cycloalkyl, aryl, halogens, alkoxy, phenoxy, and ketonic. In accordance with this invention, the alpha-aryl-propionic acid is produced by carbonylating the 1-arylethyl halide with carbon monoxide in an acidic aqueous medium and in the presence of a palladium catalyst and dissociated halide ions.
While the process of the present invention can be employed to produce any of the alpha-arylpropionic acids which would be encompassed by above structural formula, the invention is particularly useful in the production of pharmaceutical products. Products of this class, such as for example, 2-(4xe2x80x2-isobutylphenyl)propionic acid, i.e., ibuprofen, and 2-(6xe2x80x2-methoxy-2xe2x80x2-naphthyl)propionic acid, i.e., naproxen, are of special interest to the pharmaceutical industry as anti-inflammatory and analgesical agents.
The carbonylation reaction, in general, proceeds in accordance with equation (I): 
wherein AR represents phenyl or polynuclear aromatic such as naphthalene and which can be substituted with any of the non-reactive substituent groups described above, and X and Yxe2x88x92 are the same or different and selected from chlorine, bromine, iodine, or fluorine.
Suitable 1-arylethyl halides include 1-(4xe2x80x2-isobutylphenyl)ethyl chloride, 1-(3xe2x80x2-benzoylphenyl)ethyl chloride, 1-(2xe2x80x2-fluoro-4xe2x80x2-biphenylyl)ethyl chloride, 1-(2xe2x80x2-chloro-4xe2x80x2-biphenylyl)ethyl chloride, 1-(2xe2x80x2-fluorenyl)ethyl chloride, 1-(2xe2x80x2-xanthenyl)ethyl chloride, 1-(5H)-[1]benzopyrano[2,3b]pyridin-7-yl)ethyl chloride, 1-(2xe2x80x2-biphenylenyl)ethyl chloride, 1-(6xe2x80x2-methoxy-2xe2x80x2-naphthyl)ethyl chloride, 1-(4xe2x80x2-methoxyphenyl)ethyl chloride, 1-phenylethyl chloride.
In carrying out the carbonylation reaction, water may be present in an amount, for example, of about 1 to 600%, preferably about 10 to 300%, based on the weight of arylethyl halide initially present; the temperature of reaction may be, for example, in the range of about 10 to 225xc2x0 C., preferably about 70 to 175xc2x0 C.; the carbon monoxide pressure may be, for example, in the range of about 100 to 5000 psig, preferably about 600 to 3000 psig; and the total reaction time may be, for example, in the range of about 0.1 to 24 hours, preferably about 1 to 10 hours.
The palladium catalyst employed may or may not be complexed with at least one ligand. Some palladium catalysts which may be used wherein the palladium is complexed with an appropriate ligand are as follows: bis(triphenylphosphine)dichloro complex, bis(tributylphosphine)dichloro complex, bis(tricyclohexylphosphine)dichloro complex, pi-allyltriphenylphosphinedichloro complex, triphenylphosphine-piperidinedichloro complex, bis(cyclohexyloxime)dichloro complex, 1,5,9-cyclododecatrienedichloro complex, bis(triphenylphosphine)dicarbonyl complex, bis(triphenylphosphine)diacetate complex, bis(triphenylphosphine)dinitrate complex, bis(triphenylphosphine)sulfate complex, 2,4-pentanedione complex, tetrakis(triphenylphosphine) complex, and complexes in which some of the ligands are carbon monoxide such as chlorocarbonylbis(triphenylphosphine) complex, all complexes of palladium. Also suitable as a catalyst is palladium metal on a suitable catalyst support such as carbon, alumina, silica, or an inert polymer which can tolerate the conditions of reaction, complexed with one or more of these foregoing ligands. The catalyst complex may be present in an amount such that the mole ratio of palladium to arylethyl halide is in the range, for example, of about 1:25 to 1:20,000, preferably about 1:75 to 1:10,000, and most preferably about 1:100 to 1:6000.
The preferred catalysts are complexes of palladium with phosphine ligands. The palladium salts and phosphine ligands making up the catalyst complexes may also be added separately to the reaction zone. In such a case, the amount of ligand added is preferably sufficient to complex with the palladium present such that the P:Pd mole ratio is equal to at least about 1:1 when the Pd:arylethyl halide mole ratio is at least about 1:5,000. However, when the latter ratio is below 1:10,000, it is necessary to use an excess of phosphine ligand such that the P:Pd ratio is at least about 2:1.
The dissociated hydrogen ions and halide ions may be conveniently added to the reaction as hydrogen halide, e.g., hydrogen chloride, hydrogen bromide, or hydrogen iodide. However, it is also possible to add the hydrogen ions and halide ions from separate sources. For example, other ionizable acids, e.g., inorganic acids, such as sulfuric acid, phosphoric acid or polyphosphoric acid, or organic acids, e.g., sulfonic acids such as p-toluenesulfonic acid, methanesulfonic acid or trifluoroacetic acid, may be used as the source of hydrogen ions. Similarly, other water-soluble and ionizable halide compounds, as for example, halide salts wherein the cation does not interfere with the reaction, e.g., alkali metal halides such as potassium and sodium chlorides, bromides, and iodides may be used as the source of halide ions. The molar ratio of hydrogen ions and halide ions to arylethyl halide each may be in the range, for example, of about 0.1 to 5, preferably about 0.2 to 2.0.
Although not necessary for the operability of the process, in some instances, it may be advantageous to utilize an organic solvent for the reaction. Suitable organic solvents which may be used in the process of this invention are, for example, ketones such as methylethyl ketone, acetone, 2-pentanone, 3-pentanone, and acetophenone, aromatic hydrocarbons such as benzene and toluene, and cyclic ethers such as tetrahydrofuran and dioxane. Ketones and ethers are the preferred solvents. The solvent may be present in a weight ratio of solvent to arylethyl halide in the range, for example, of about 0 to 1000:1, preferably about 0 to 10:1.
An inorganic salt may also be present during the reaction. Inorganic salts which may be used are, for example, those yielding anions comprising oxygen, and sulfur, phosphorus, aluminum or silicon, including such anions as hydrogensulfate, pyrosulfate, ortho-phosphate, pyrophosphate, aluminate, or silicate and cations such as sodium, potassium, calcium, or magnesium, or another cation which does not interfere with the reaction, e.g., ammonium or alkylammonium such as tetrabutylammonium. Other inorganic salts such as calcium chloride may also be added. The inorganic salt, if used, will generally be present at a concentration of, for example, about 0.1 to 50%, preferably about 1 to 2% by weight of total charge.
In addition to those mentioned previously, other additives and ligands may be added to the reaction, e.g., acetophenone and p-mercaptoacetophenone. The latter additives appear to be useful in raising the ratio of ibuprofen to corresponding linear isomer, viz., 3-(4xe2x80x2-isobutylphenyl)propionic acid (3-IPPA), obtained by the method of this invention.
The 1-arylethyl halides employed as the starting materials in the production of the 2-arylpropionic acids can be obtained from any commercial source or formed by any conventional process. For example, the chlorides can be produced by reacting the 1-arylethyl alcohols with hydrogen chloride in the liquid phase in the presence of a metal chloride catalyst such as calcium chloride, sodium chloride, potassium chloride, etc. Known techniques for forming the bromides and iodides may also be used and include the reaction of the respective alcohols with phosphorus tribromide in a basic medium. In the formation of ibuprofen, the alpha-arylethyl halide may be formed by reacting the hydrogen halide with 1-(4xe2x80x2-isobutylphenyl)ethanol (IBPE). Another method of forming the 1-arylethyl halide would be to react vinylbenzenes, e.g., styrene, with a hydrogen halide.
A particularly useful method of obtaining the 1-aryl-ethyl halides is by the haloalkylation of aromatic compounds such as benzene and derivatives thereof. The process is known and disclosed in U.S. Pat. Nos. 2,859,253 and 3,933,326, and is further described in xe2x80x9cFreidal-Crafts and Related Reactionsxe2x80x9d, Vol. 2, Part 2, page 659, G. Olah, editor, all of which are herein incorporated by reference. The process involves reacting the aromatic compound with both an alkylating agent and a halide in the presence of a Lewis acid. Effective haloalkylating agents include acetaldehyde, paraldehyde, 1,1-dimethoxyethane, di-(1-chloroethyl)ether with hydrogen chloride, hydrogen bromide or hydrogen iodide. Generally, the mole ratio of the haloalkylating reagent to aromatic compound will range between about 0.5 to 2.5:1 and, preferably from about 1.0 to 1.5:1. Lewis acids which can be employed include ZnCl2, SnCl4, AlCl3, BF3, FeCl3, TiCl4, as well as protic acids such as HCl, HBr, HI, HF, H2SO4, H3PO4, ClSO3H, and acetic acid. Molar ratios of Lewis acid to aromatic substance may be from about 1:1 to about 5:1 and, preferably between about 2 to 3:1. If a gaseous hydrogen halide is used, it can be bubbled at a suitable rate.
The reaction can be carried out with or without a solvent. The reaction may be carried out with excess aromatic compound serving as the solvent or with an inert solvent such as acetic acid, diethyl ether, tetrahydrofuran, dimethyl formamide, carbon tetrachloride, chloroform, methylene chloride, chloroethyl ether, nitrobenzene, and carbon disulfide. The amount of solvent employed is not critical. The temperature of the reaction may range from between about xe2x88x9270 to 150xc2x0 C. and preferably from about 0 to about 80xc2x0 C. Reaction time will be between about 1 to about 48 hours and, preferably between 3 to 24 hours.
The haloalkylation of aromatic compounds provides an advantageous route to the formation of ibuprofen from isobutylbenzene. Thus, it is now possible to produce ibuprofen from isobutylbenzene in two steps. The first step would be haloethylation of isobutylbenzene by the method as described above. The 1-arylethyl halide which is formed can then be carbonylated as previously described to ibuprofen.